Abruptio placentae (AP), the premature separation of the placenta, is a life threatening obstetric condition that complicates roughly 1-2 percent of all pregnancies. Pathophysiologic mechanisms involved in AP (and related perinatal disorders - preterm birth, preeclampsia, and intrauterine growth restriction) include uteroplacental ischemia, underperfusion, chronic hypoxia, and infarctions. On this basis, investigators have begun to conceptualize abruption as an ischemic placental disorder characterized by acute and chronic pathophysiological features. Furthermore, evidence suggests that transient activation of the sympathetic nervous system might trigger AP. The etiology of AP remains unknown, though results from previous studies suggest some risk factors and emerging evidence suggest a significant genetic component in the pathogenesis of AP. At present, neither an accurate prediction nor prevention of AP is possible. We seek to increase our understanding of the epidemiology and pathophysiology of AP by conducting a large multi-center epidemiologic study of AP in Lima, Peru. We will use the self-matched case-crossover design to evaluate the acute effects of: 1) maternal smoking and alcohol consumption; 2) physical exertion; 3) sexual activity; 4) abdominal trauma secondary to falls or motor vehicle crashes; and 5) exposure to intimate partner violence as potential triggers of AP. The risk of AP will be assessed during pre-specified hazard periods. We will also use the case-control replicative (two stage) study design to study genetic variants that influence the pathogenesis of AP in well characterized 900 mother-infant abruption case pairs and 900 mother-infant control pairs. We plan to focus on specific gene pathways, including coagulation, fibrinolysis, platelet function, infection and inflammation, angiogenesis, folate metabolism, and the renin-angiotensin systems that have previously been associated with AP. In Stage 1, we will use a high-density single nucleotide polymorphism (SNP) 1536-chip on the 1st half of samples to scan maternal and infant SNPs and SNP haplotypes for association with AP. In Stage 2, we will select ~200 of the most pertinent candidate SNPs for replication in the 2nd half of samples. We hypothesize that genes associated with substantial relative risk of AP in Stage 1 will replicate in the independent sample set used in Stage 2. Results from these proposed studies will reveal new insights into the pathophysiology of AP by formally exploring possible interactions between prolonged and habitual exposures (e.g., habitual alcohol consumption and physical activity) and triggering effects of factors such as binge drinking or extreme physical exertion. Results will also yield new insights into the inherited genetic bases of AP. Collectively, these new insights may facilitate the development of new approaches for the primary prevention of AP (at the public health level) and may also facilitate the development of new therapies and methods for diagnosis. PUBLIC HEALTH RELEVANCE: Abruptio placentae (AP), is of global public health importance in large part because of its association with adverse outcomes in newborns and mothers including preterm delivery, fetal death, maternal hemorrhagic shock, and renal failure. We will use the self-matched case-crossover design to study the transient effects of putative triggers of AP; and we will use the case-control design to study genetic variants that influence the pathogenesis of AP in 900 mother-infant abruption case pairs and 900 mother-infant control pairs. Results from our research have a very high potential for yielding etiologic and clinical information that may prove to be effective in the identification of women at greatest need of specific preventive interventions and specialized clinical care.